An estimated 5.7 million people in the U.S. have heart failure and more than 292,000 die from heart failure-related complications each year. While much is known about the mechanisms of cardiac hypertrophic growth and subsequent decompensation leading to failure, few therapeutic strategies are available, and these are aimed primarily at relieving symptoms, preventing hospitalization, and improving the quality of life of patients, with little overall effect on mortality. Recent research has provided new insights into the molecular signaling pathways involved in the progression of the disease;however, heart failure remains a complex multifactorial problem. A comprehensive mechanistic understanding of heart failure requires not just elucidation of targets/pathways modified during the progression of the disease, but an integrative understanding of how alterations at the level of genes and proteins affect the sophisticated interplay between the electrophysiological, Ca2+ handling, and energetic subsystems of the cardiac cell. This proposal brings together leaders in the areas of excitation-contraction coupling, mitochondrial biology, redox modulation, proteomics, and computational biology to investigate how the remodeling of ion transport pathways and mitochondrial proteins contribute to maladaptive responses in a pressure-overload model of hypertrophy, which progresses to heart failure over several weeks. The central hypothesis to be explored is that alterations in Ca2+m dynamics not only contribute to impaired energy supply and demand matching following pressure-overload, but also significantly compromise the pathways responsible for handling reactive oxygen (ROS) and nitrogen (RNS) species in the mitochondria and the cell. This imbalance results in ROS/RNS-dependent modifications of key proteins involved in EC coupling and mitochondrial oxidative phosphorylation, with concomitant effects on function that contribute to cellular injury or death. A vicious circle of these complex deleterious interactions could thus mediate decompensation of the failing heart.

Public Health Relevance

MITOCHONDRIAL DYSFUNCTION IN CARDIAC HYPERTROPHY AND FAILURE 1. Project Narrative Heart failure is a leading cause of death whose incidence is increasing despite overall decreases in mortality in the United States. Current treatments are inadequate, but new evidence has implicated changes in mitochondria, the powerhouses of the cardiac cell, in the progression and severity of the disease. This proposal will investigate the central role of mitochondria in controlling the heart's response to increased blood pressure and how to prevent the failure of energy production that leads to the death of patients with cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL101235-01
Application #
7847834
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Liang, Isabella Y
Project Start
2010-05-01
Project End
2014-03-31
Budget Start
2010-05-01
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$700,977
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kanaporis, Giedrius; Blatter, Lothar A (2017) Membrane potential determines calcium alternans through modulation of SR Ca2+ load and L-type Ca2+ current. J Mol Cell Cardiol 105:49-58
Bovo, Elisa; Huke, Sabine; Blatter, Lothar A et al. (2017) The effect of PKA-mediated phosphorylation of ryanodine receptor on SR Ca2+ leak in ventricular myocytes. J Mol Cell Cardiol 104:9-16
Foster, D Brian; Liu, Ting; Kammers, Kai et al. (2016) Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death. J Proteome Res 15:3009-28
Goh, Kah Yong; Qu, Jing; Hong, Huixian et al. (2016) Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes. Cardiovasc Res 109:79-89
Kanaporis, Giedrius; Blatter, Lothar A (2016) Calcium-activated chloride current determines action potential morphology during calcium alternans in atrial myocytes. J Physiol 594:699-714
O'Rourke, Brian; Liu, Ting; Foster, D Brian (2016) Seeing the Forest for the Trees. Circ Res 119:1170-1172
Wei, An-Chi; Liu, Ting; O'Rourke, Brian (2015) Dual Effect of Phosphate Transport on Mitochondrial Ca2+ Dynamics. J Biol Chem 290:16088-98
Seidlmayer, Lea K; Juettner, Vanessa V; Kettlewell, Sarah et al. (2015) Distinct mPTP activation mechanisms in ischaemia-reperfusion: contributions of Ca2+, ROS, pH, and inorganic polyphosphate. Cardiovasc Res 106:237-48
Clancy, Colleen E; Chen-Izu, Ye; Bers, Donald M et al. (2015) Deranged sodium to sudden death. J Physiol 593:1331-45
Hohendanner, Felix; Maxwell, Joshua T; Blatter, Lothar A (2015) Cytosolic and nuclear calcium signaling in atrial myocytes: IP3-mediated calcium release and the role of mitochondria. Channels (Austin) 9:129-38

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